Diastereoselective Synthesis of Trifluoromethylated γ‐Butyrolactones via N‐Heterocyclic Carbene‐Catalyzed Conjugated Umpolung of α,β‐Unsaturated Aldehydes

Abstract

Abstract:The N-heterocyclic carbene-catalyzed conjugate umpolung of differently substituted a,bunsaturated aldehydes is described. Coupling of these compounds with a variety of trifluoromethylated ketones results in the selective formation of fluorinated g-butyrolactones. Using thiazolium-derived N-heterocyclic carbenes, the unlike stereoisomers are formed predominantly, whereas the imid-A C H T U N G T R E N N U N G azol-2-ylidene IMes results in lower selectivities and the preferred formation of the like isomer.Keywords: g-butyrolactones; N-heterocyclic carbenes; organocatalysis; organofluorine compounds; trifluoromethyl substitution; umpolung The inversion of polarity (umpolung) of electrophilic substrates by addition of nucleophilic catalysts is a versatile and synthetically useful concept in organic chemistry. Recently, the N-heterocyclic carbene [1] (NHC)-catalyzed, [2] chemo-and stereoselective umpolung of a,b-unsaturated aldehydes was developed, giving access to b- [3] and g-butyrolactones, [3,4] bicyclob-lactams, [5] g-lactams, [6] and cyclopentene derivatives. [7,8] The proposed mechanism for the formation of g-butyrolactones proceeds through a conjugate enamine, which represents a homoenolate equivalent (Scheme 1). The intermediates of the catalytic cycle could be validated by ESI-MS experiments.[4d]In our original publication, [4c] we reported the IMes-catalyzed conjugate umpolung of a,b-unsaturated aldehydes and the use of a,a,a-trifluoroacetophenone as the electrophilic reaction partner. This resulted in the formation of trifluoromethylated g-butyrolactones, albeit, with low diastereoselectivities.Fluorinated organic compounds have found widespread applications as active ingredients in drugs or crop protection agents, as materials or in catalysis [9] Scheme 1. Formation of g-butyrolactones by conjugate umpolung.

A Family of Thiazolium Salt Derived N‐Heterocyclic Carbenes (NHCs) for Organocatalysis: Synthesis, Investigation and Application in Cross‐Benzoin Condensation

“…[14] In addition, a diastereoselective synthesis of trifluoromethylated γ-butyrolactones using thiazol-2-ylidenes as optimal catalysts has been reported. [15] A first breakthrough in terms of the compatibility of NHCs with transition-metal catalysts was reported by Hamada and co-workers, the one-pot sequential multi-catalytic Pd-catalyzed allylic amination/NHC-catalyzed Stetter reaction cascade using activated olefins. [16] Moreover, an investigation by Rose and Zeitler clearly demonstrated the great potential of the compatibility of thiazolylidenes with organic oxidants such as azobenzene in enabling oxidative lactonization chemistry.…”

Intermolecular N‐Heterocyclic Carbene Catalyzed Hydroacylation of Arynes

“…Our present study commenced with the NHC-catalyzed reaction of 4-bromobenzaldehyde (1 a) with the aryne generated in situ from 2-trimethylsilylaryl triflate (2 a) and 2.0 equivalents each of KF and [18]crown-6. Reacting these substrates in the presence of the carbene generated from 4 [8,11] by deprotonation using K 2 CO 3 resulted in the formation of 4-bromobenzophenone (3 a) in 60 % yield (based on GCMS; Table 1, entry 1). Remarkably, in contrast to this NHC, other common NHCs derived from 5-8 are far less effective (entries 2-5).…”

Eine intermolekulare, durch N‐heterocyclische Carbene katalysierte Hydroacylierung von Arinen

“…KF und [18]Krone-6. In Gegenwart der Carben-Vorstufe 4 [8,11] Unter den optimierten Bedingungen wurden keine Produkte der direkten Addition des NHC oder des Aldehyds [6] an das elektrophile Arin beobachtet. Ausgehend von den optimierten Reaktionsbedingungen wurde die Substratbreite der neuartigen Insertionsreaktion von Arinen untersucht (Schema 1).…”

“…KF und [18]Krone-6. In Gegenwart der CarbenVorstufe 4 [8,11] [c] [a] Standardbedingungen: 1 a (0.25 mmol), 2 a (0.3 mmol), NHC·HX (10 Mol-%), K 2 CO 3 (20 Mol-%), KF (0.5 mmol), [18]Krone-6 (0.5 mmol), THF (1.0 mL), 25 8C und 4 h. Bn = Benzyl, DBU = 1,8-Diazabicyclo- [5.4.0]undec-7-en, DME = 1,2-Dimethoxyethan, Mes = 2,4,6-Trimethylphenyl. [b] Die Ausbeuten wurden durch GC-MS-Analyse des Rohprodukts unter Verwendung von Mesitylen als internem Standard bestimmt.…”